Endoplasmic stress response, the unfolded protein response (UPR), is a homeostatic signaling pathway comprising transmembrane sensors that get activated upon alterations in ER luminal environment. Studies suggest a relation between activated UPR pathways and several disease states such as Parkinson, Alzheimer, inflammatory bowel disease, tumor growth, and metabolic syndrome. Diabetic peripheral neuropathy (DPN), a common microvascular complication of diabetes-related chronic hyperglycemia, causes chronic pain, loss of sensation, foot ulcers, amputations, allodynia, hyperalgesia, paresthesia, and spontaneous pain. Factors like disrupted calcium signaling, dyslipidemia, hyperglycemia, inflammation, insulin signaling, and oxidative stress disturb the UPR sensor levels manifesting as DPN. We discuss new effective therapeutic alternatives for DPN that can be developed by targeting UPR pathways like synthetic ER stress inhibitors like 4-PhenylButyric acid (4-PBA), Sephin 1, Salubrinal and natural ER stress inhibitors like Tauroursodeoxycholic acid (TUDCA), Cordycepin, Proanthocyanidins, Crocin, Purple Rice extract and cyanidin and Caffeic Acid Phenethyl Ester (CAPE).